Abstract Melanoma is the most aggressive and the deadliest form of skin cancer with very limited treatment options due to resistance to conventional chemotherapy. Discovery of BRAF mutation ( ?60 % of melanoma patients) and BRAF inhibitors in recent years proved to be breakthroughs in the field of melanoma cancer treatment. Unfortunately, patients developed drug resistance and eventually relapsed within an average of 7 months after vemurafenib (VF) therapy. Combination of BRAFi and MEKi is currently in clinical practice and show remarkable tumor response rate and prolong patient survival leading to a new era of melanoma therapy. But Off target toxicities and cross-resistance limits clinical potential of this approach. Consequently, there is a growing and urgent need to develop novel or alternative therapeutic approaches for the treatment of melanoma. Recently, researchers have developed a BET degrading molecules - BRD4 PROTAC (BPRO) (known as ARV-825), which selectively degrades BRD4 protein instead of mere inhibiting it. Bromodomain degraders or any other PROTAC molecules were never investigated on VF resistant melanoma cancer. Preliminary studies in our laboratory have revealed two very interesting findings; (1) We observed that BPRO is significantly more cytotoxic in VF resistant SK-MEL-28 and A375 compared to parent SK-MEL-28 and A375 and (2) BPRO remarkably reduced the IC50 of VF in both the cell lines. Considering the potential of BPRO - alone and in combination with VF in the treatment of BRAFi resistant melanoma, we decided to develop a translational oral nanoformulation co-loaded with VF and BPRO. The main goal of proposed investigation is to develop an orally bioavailable formulation of VF and BPRO for improved treatment of parent and BRAFi resistant melanoma cancer. To achieve this goal, we propose two specific aims; Specific aim 1. Optimization and characterization of formulation for permeability and oral bioavailability. Specific aim 2. In vivo anticancer efficacy study of optimized NANOVB in parent and BRAFi resistant melanoma tumor bearing mice.